This invention relates to a new surfactant for perfluorocarbon (PFC) microemulsions.
PFC emulsions are well known and have great promise as blood substitutes and other medical applications. Several properties critical to the success of a PFC emulsion are primarily due to the specific surfactant employed. For example, the emulsion must be stable so that it can be stored for long periods, preferably for many months and at room temperature. If the emulsion particles agglomerate during storage, or in the worst case the emulsion separates, there is no means in most hospitals for re-emulsifying it to the original condition. Although factors such as the specific PFC and the amount of PFC contribute to emulsion stability, the stability is largely determined by the surfactant.
Additionally, the emulsion particles must be sufficiently small to pass through the smallest capillaries without plugging them. Current thinking is that the PFC particles should be smaller than 0.2 micron, preferably less than 0.1 micron. Although the ultimate particle size achievable depends somewhat on the energy input in the emulsification step, it depends mainly on the specific emulsifier employed.
In respect of stability and particle size, the emulsion ideally is a microemulsion. Microemulsions behave as solutions i.e., as a single phase. They are well known in the enhanced oil recovery art and have achieved some recognition in PFC emulsions. See, e.g., U.S. Pat. No. 3,989,843 to Pierre Chabert et al. Such emulsions can be formed with relatively mild agitation and are stable for months over a specified temperature range. Above or below this range, the emulsion will deteriorate into two phases, but if returned to the specified temperature range they revert to the stable microemulsion form upon such mild agitation as hand shaking. Ideally, the range of temperature stability encompasses the intended use which for internal medical application is about 18.degree.-43.degree. C., i.e., from slightly below room temperature to the temperature of a high fever.
Another necessary emulsion characteristic is the obvious overriding requirement of any medical composition that it be non-toxic. The toxicity or lack of toxicity of a PFC emulsion is attributable in large part to that of the surfactant, since the preferred fluorocarbons described above show very minimal toxicity. The surfactant toxicity is generally unpredictable and bears little relationship to its emulsification ability. Some, such as the amine oxides, make outstanding emulsions from a strictly technical standpoint, but are quickly ruled out, nonetheless, because of their generally high toxicity.
There are other important in vivo characteristics of a PFC emulsion. One is the tendency of the emulsion to not cause crenation of the red blood cells. Crenation is a change in the shape of these cells from generally circular to a horned or starry shape. The latter cells do not pass through the arteries as well. Ideally, the PFC emulsion does not cause any crenation, or at least limits it to a short duration, e.g., less than 30 minutes.
A further in vivo attribute is lack of aggregation of the PFC particles in the emulsion. This refers to the tendency of the particles, in the presence of blood, to form clusters of particles. Although this gathering into clusters is distinct from the phenomenon where several particles merge into a single larger particle, the clusters have most of the same disadvantages; they increase the emulsion viscosity, and they also do not traverse the arteries as well.
Another necessary attribute is that the emulsion not cause hemolysis, which is a deterioration of the red blood cell membrane with an attendant loss of hemoglobin.